Excessive proinflammatory cytokine production by activated glia is a contributor to pathophysiology progression in CMS diseases such as Alzheimer's disease (AD). The p38 mitogen activated protein kinase (MAPK) family, especially p38?MAPK, are important signal transduction regulators of proinflammatory cytokine production and were identified as in vivo druggable targets for peripheral inflammatory disorders. However, much less is known about the potential in vivo involvement of p38?MAPK, or the closely related isoform p38?MAPK, in the increased production of CNS proinflammatory cytokines. This project will test the hypothesis that p38?MAPK is a key in vivo contributor to increased CNS proinflammatory cytokine production in response to an AD-relevant stressor, and is an in vivo CNS target for a selective, small molecule inhibitor with potential for future development into disease-altering therapeutics. Specific aim 1: I will test the hypothesis that p38pMAPK does not contribute to A?-induced proinflammatory cytokine up-regulation and associated synaptic dysfunction. I will use an in vivo AD-relevant stressor, A? infusion, in wildtype (WT) and p38? knockout (KO) mice, and measure the hippocampus levels of proinflammatory cytokines, synaptic marker proteins, and hippocampal-dependent behavioral deficits. Specific aim 2:1 will test the hypothesis that p38? MAPK is a major contributor to the therapeutic effects of a brain-penetrant, p38 MAPK inhibitor. I will use an AD-relevant stressor, A? infusion, in WT, p38?MAPK (T106M) and p38?MAPK(T106M) knockin (Kl) mice, which are resistant to p38MAPK inhibitors, in the presence or absence of MW01-2-069A-SRM, a CNS-penetrant and selective p38?.inhibitor. I will measure the same proinflammatory cytokines, synaptic marker proteins, and hippocampal-dependent behavioral deficits as Aim 1. There is a current need for therapeutics for inflammatory-mediated CNS diseases, including AD. This study will characterize the in vivo mechanistic relationships among AD-relevant activation of p38?MAPK-mediated signal transduction pathways, glia proinflammatory cytokine upregulation, and the associated neuropathophysiology, while providing a firmer foundation for on-going and future AD-related drug development campaigns.